A Natural History Study of RYR1-Related Disorders

STUDY DESCRIPTION:

This prospective natural history study seeks to characterize the clinical manifestations and course of Ryanodine Receptor 1 -related disorders (RYR1-RD). RYR1-RD include a wide range of rare congenital and adult-onset neuromuscular phenotypes that are typically slowly progressive. The study is observational and comprises a primary data collection phase (Years 1-3) and extended follow-up phase (Years 4-5), stratified into centralized (ambulatory) and decentralized (non-ambulatory) arms. During each phase, there will be one visit per year. The study will enhance the foundational knowledge of RYR1-RD and support clinical trial readiness.

OBJECTIVE:

Primary:

Characterize phenotype and disease course over a three-year period

Secondary:

Characterize phenotype and disease course over an extended (2-year) period (total 5 years)

Exploratory:

1. Investigate potential biomarkers of disease status and progression 2. Explore clinical meaningfulness thresholds for research assessments 3. Extract common data elements from existing medical records (real-world evidence)

ENDPOINTS:

Primary:

Change from baseline to Year 3 in:

Motor function and performance * Motor Function Measure (MFM) sub-domains (percent of maximum score) * Six-minute walk test (meters travelled with percent predicted) * Timed functional tests (ascend four stairs, descend four stairs, supine to stand) (seconds) * Grip and pinch strength (kg and percent predicted) * Performance of Upper Limb (PUL) * Accelerometry (wearable sensor) * Quantitative muscle assessment * Brooke and Vignos assessment

Pulmonary function * Forced vital capacity (percent reference norm) * Forced expiratory volume at 1 second (percent reference norm) * Slow vital capacity (Liters) * Maximal voluntary ventilation (Liters) * Maximum inspiratory pressure (MIP) * Maximum expiratory pressure (MEP)

Patient-reported outcomes * PROMIS-57 Profile (subscale and overall t-scores); adults - depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles * PROMIS Ped-25 Profile (subscale and overall t-scores); 8 - 17 y * PROMIS Parent Proxy 25 Profile - Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5 - 7 y * PROMIS Upper Extremity - Short Form 7a * PROMIS Pediatric Upper Extremity - Short Form 8a * PROMIS Parent Proxy Upper Extremity - Short Form 8a * Physical Activity Questionnaire for Children (PAQ-C); 8 - 13 y * Physical Activity Questionnaire for Adolescents (PAQ-A); 14 - 17 y * International physical activity questionnaire (IPAQ); adults

Ophthalmology * Visual acuity * Dilated ophthalmology exam at baseline only * Extraocular motility assessment * Marginal reflex distance (Ptosis) * Optical Coherence Tomography * Ancillary testing, imaging, and repeat dilated exams as indicated, based on assessment and discretion of clinician

Secondary:

Change from baseline to Year 5 in:

Motor function and performance * Motor Function Measure (MFM) sub-domains (percent of maximum score) * Six-minute walk test (meters travelled with percent predicted) * Timed functional tests (ascend four stairs, descend four stairs, supine to stand) (seconds) * Grip and pinch strength (kg and percent predicted) * Performance of Upper Limb (PUL) * Accelerometry (wearable sensor) * Quantitative muscle assessment * Brooke and Vignos assessment

Pulmonary function * Forced vital capacity (percent reference norm) * Forced expiratory volume at 1 second (percent reference norm) * Slow vital capacity (Liters) * Maximal voluntary ventilation (Liters) * Maximum inspiratory pressure (MIP) * Maximum expiratory pressure (MEP)

Patient-reported outcomes * PROMIS-57 Profile (subscale and overall t-scores); adults - depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles * PROMIS Ped-25 Profile (subscale and overall t-scores); 8 - 17 y * PROMIS Parent Proxy -25 Profile Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5 - 7 y * PROMIS Upper Extremity - Short Form 7a * PROMIS Pediatric Upper Extremity - Short Form 8a * PROMIS Parent Proxy Upper Extremity - Short Form 8a * Physical Activity Questionnaire for Children (PAQ-C); 8 - 13 y * Physical Activity Questionnaire for Adolescents (PAQ-A); 14 - 17 y * International physical activity questionnaire (IPAQ); adults

Ophthalmology * Visual acuity * Dilated ophthalmology exam at baseline only * Extraocular motility assessment * Marginal reflex distance (Ptosis) * Optical Coherence Tomography * Ancillary testing, imaging, and repeat dilated exams as indicated, based on assessment and discretion of clinician

Exploratory:

Biomarkers

Including but not limited to: * Plasma NAD plus, NADH * Plasma GSH, GSSG * Plasma cytokines * Serum creatine phosphokinase * Urine and plasma 15-F2t isoprostane * Urine 8OHdG * PBMC (Peripheral Blood Mononuclear Cell) * Near infrared spectroscopy (muscle tissue oxygenation) * Dixon MRI of lower extremity * Optional skin punch biopsy (fibroblast culture) * Muscle ultrasound * Electrical impedance myography (EIM)

• Characterize phenotype and disease course over an extended (2-year) period (total 5 years).Collect exploratory biomarker data. [Срок оценки: 5 years]